AEGiS-13IAC: Aminoglycoside-arginine conjugates: novel multifunctional HIV Tat antagonists.

13th International AIDS Conference

Durban, South Africa - July 9-July 14, 2000

Aminoglycoside-arginine conjugates: novel multifunctional HIV Tat antagonists.

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. TuOrA409)

Lapidot A, Litovchick A, Borkow G
A. Lapidot, Weizmann Institute of Science, Prof. Aviva Lapidot, Dept. Organic Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel, Israel, Tel.: +972-8-934-3413, Fax: +972-8-934-4142, E-mail: aviva.lapidot@weizmann.ac.il

BACKGROUND: HIV Tat protein is a key factor of HIV transcription, an immunosuppresor, an activator of quiescent T cells for productive HIV-1 infection, a chemokine analog and an up-regulator of HIV-1 coreceptors expression. We have recently designed and synthesized a novel group of peptidomimetic compounds, aminoglycosides-arginine conjugates (AAC, mw ~ 1000 Da), which mimic HIV Tat capacity to bind to HIV TAR RNA and inhibit HIV-1 proliferation in cell culture. We here present a new member of AAC group, neomycin B-arginine conjugate, NeoR, and its enhanced anti-HIV activity.

METHODS: Design and synthesis of NeoR. Measurements of the anti-HIV activity of NeoR in lymphoid cell lines and peripheral blood mononuclear cells (PBMC) were done at different stages of infection. NeoR capacity to inhibit HIV Tat functions, such as immunosuppression, alteration of HIV co-receptor expression in PBMC was determined by flow cytometry.

RESULTS: NeoR inhibited different HIV-1 strains in cell culture (EC50 2-4 m M). Inhibition of anti-CD3-induced PBMC proliferation by 7 nM of HIV Tat was neutralized by 1 m M NeoR. Similarly, the decrease in CD8+ cells, caused by incubation of PBMC with 20 nM HIV Tat, was abolished by 5 m M NeoR. Furthermore, the up-regulation of CXCR4 expression in human peripheral monocytes caused by 14 nM HIV Tat was abolished in the presence of 2 m M NeoR. Flow cytometry analysis revealed that NeoR competes with monoclonal antibody binding to CXCR4, indicating that NeoR binds to this HIV-1 coreceptor.

CONCLUSIONS: NeoR is significantly more active than our previous AAC (e.g. arginine conjugates with gentamicin C, R3G, and kanamycin A, R4K). AAC, and specifically NeoR, inhibit different stages of HIV infection, therefore they are promising multifunctional lead HIV Tat antagonists. Litovchick A., Evdokimov, A.G. and Lapidot, A. (1999) FEBS Letts 445, 73-9; (2000) Biochemistry, in press.

Keywords: AEGIS, HIV Infections, HIV-1, Framycetin, Gene Products, tat, Arginine, HIV Seropositivity, Kanamycin, Anti-Bacterial Agents, Monocytes, Cell Line, Gentamicins, Greece, gentamicin C, Human
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